Haemostasis Flashcards
What is haemostasis?
the cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult
What is haemostasis for?
Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
enable tissue repair
What are the stages of haemostasis?
Primary
Secondary
Fibrinolysis
What are the steps of haemostasis?
Vessel constriction
Formation of an unstable platelet plug
Stabilisation of plug with fibrin
Vessel repair and dissolution of clot
Why is it important to understand haemostatic mechanisms?
Diagnose and treat bleeding disorders
Control bleeding in individuals who do not have an underlying bleeding disorder
Identify risk factors for thrombosis
Treat thrombotic disorders
Monitor the drugs that are used to treat bleeding and thrombotic disorders
What is low platelets known as?
thrombocytopenia
What causes low platelets?
Bone marrow failure eg: leukaemia, B12 deficiency
Accelerated clearance eg: immune (ITP), Disseminated Intravascular Coagulation (DIC)
Pooling and destruction in an enlarged spleen
What causes impaired function of platelets?
Hereditary absence of glycoproteins or storage granules (rare)
Acquired due to drugs: aspirin, NSAIDs, clopidogrel (common)
What are conditions that impaired platelet function?
Glanzmann’s thrombasthenia
Bernard Soulier syndrome
Storage Pool diseas
What are the two functions of VWF?
Binding to collagen and capturing platelets
Stabilising Factor VIII
Factor VIII may be low if VWF is very low
What is VWD?
Von Willebrand disease
Hereditary decrease of quantity +/ function (common)
Acquired due to antibody (rare)
VWD is usually hereditary (autosomal inheritance pattern)
Deficiency of VWF (Type 1 or 3)
VWF with abnormal function (Type 2)
What is the third aspect that a defect in can affect haemostasis?
The vessel wall
What causes defects in the vessel wall?
Inherited (rare)
Hereditary haemorrhagic telangiectasia
Ehlers-Danlos syndrome
and other connective tissue disorders
What are the clinical features of primary haemostasis bleeding?
Immediate
Prolonged bleeding from cuts
Nose bleeds (epistaxis):prolonged > 20 mins
Gum bleeding: prolonged
Heavy menstrual bleeding (menorrhagia)
Bruising (ecchymosis), may be spontaneous/easy
Prolonged bleeding after trauma or surgery
What are petechia and purpura?
caused by bleeding under the skin
Purpura do not blanch when pressure is applied
What is a feature (to diagnose) of thrombocytopenia?
Petechia
What are tests for disorders of primary haemostasis?
Platelet count, platelet morphology
Bleeding time (PFA100 in lab)
Assays of von Willebrand Factor
Clinical observation
Note –coagulation screen (PT, APTT) is normal (except more severe VWD cases where FVIII is low)
What are the treatments if it is failure of production?
Failure of production/function Replace missing factor/platelets e.g. VWF containing concentrates i) Prophylactic ii) Therapeutic Stop drugs e.g. aspirin/NSAIDs
What are treatments for immune destruction? (including ITP)
Immune destruction
Immunosuppression (e.g. prednisolone)
Splenectomy for ITP
What are treatments for increased consumption?
Treat cause
Replace as necessary
What are some additional haemostatic treatments?
- Desmopressin (DDAVP)
Vasopressin analogue
2-5 fold increase in VWF (and FVIII)
releases endogenous stores (so only useful in mild disorders) - Tranexamic acid
Antifibrinolytic - Fibrin glue/spray
- Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)
What is the role of coagulation?
to generate thrombin (IIa), which will convert fibrinogen to fibrin
What would a deficiency in any coagulant factor cause?
Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation
What are hereditary causes of coagulation factor production?
Factor VIII/IX: haemophilia A/B
What are acquired causes of disrupted coagulation factor production?
Liver disease
Anticoagulant drugs
Warfarin
Direct Oral Anticoagulants (DOACs)
What are acquired causes of dilution causing disorder of coagulation?
Blood transfusion
What are acquired causes of increased consumption?
Disseminated intravascular coagulation (DIC) – common
Immune – autoantibodies – rare
Wha are the features of inherited coagulation disorders?
Haemophilia A (Factor VIII deficiency) Haemophilia B (Factor IX deficiency) sex linked 1 in 104 births Others are very rare (autosomal recessive)
What should be avoided in patients with haemophilia?
IM injections
Why are different coagulation factor deficiencies not all the same?
Factor VIII and IX (Haemophilia)
Severe but compatible with life
Spontaneous joint and muscle bleeding
Prothrombin (Factor II)
Lethal
Factor XI
Bleed after trauma but not spontaneously
Factor XII
No bleeding at all
Why does liver failure cause coagulation disorders?
Most coagulation factors are synthesised in the liver
Why does dilution produce coagulation disorders?
Red cell transfusions no longer contain plasma
Major haemorrhage requires transfusion of plasma as well as red cells and platelets
What are the features of increased consumption?
Generalised activation of coagulation – Tissue factor
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors
Platelets consumed - thrombocytopenia
Activation of fibrinolysis depletes fibrinogen – raised D-dimer
(a breakdown product of fibrin)
Deposition of fibrin in vessels causes organ failure
What are the clinical features of coagulation disoders?
superficial cuts do not bleed (platelets)
bruising is common, nosebleeds are rare
spontaneous bleeding is deep, into muscles and joints
bleeding after trauma may be delayed and is prolonged
Bleeding frequently restarts after stopping
What are the tests for coagulation disorders?
Screening tests (‘clotting screen’)
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Full blood count (platelets)
Coagulation factor assays (for Factor VIII etc)
Tests for inhibitors
What are the different types of factor replacement therapy?
Fresh Frozen Plasma
Cryoprecipitate
Factor Concentrates
Recombinate forms of FVIII and FIX
What are the features of FFP?
Contains all Coagulation factors
What are the features of cryoprecipitate?
Rich in Fibrinogen, FVIII, VWF, Factor XIII
What are the features of factor concentrates?
Concentrates available for all factors except factor V.
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
Wen are recombinant forms of FVIII and FIX used?
‘On Demand’ to treat bleeds
Prophylaxis to prevent bleeds
How to disorders of thrombosis present?
Pulmonary embolism
Deep vein thrombosis
What are the features of PE?
Tachycardia Hypoxia Shortness of breath Chest pain Haemopysis Sudden death
What are the features of DVT?
Painful leg Swelling Red Warm May embolise to lungs Post thrombotic syndrome
What type of thrombosis are PE and DVT?
Venouse
What is thrombosis?
Intravascular coagulation Inappropriate coagulation Venous (or arterial) Obstructs flow May embolise to lungs
What is Virchow’s triad?
Three contibutpry factors to thrombosis Blood (dominant in venous) Vessel wall (dominant in arterial) Blood flow (both)
What is thrombophilia?
Increased risk of thrombosis
What is indicative of thrombosis?
Thrombosis at young age
‘spontaneous thrombosis’
Multiple thromboses
Thrombosis whilst anti-coagulated
What are anticoagulant proteins?
Antithrombin
Protein C
Protein S
What is the role of vessel wall in thrombosis?
We know little about the role of the vessel wall in venous thrombosis.
Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression altered in inflammation (TM, EPCR, TF)
What are the risk factors for venous thrombosis?
Age
Genetic
Environmental
How to you prevent thrombosis?
Assess and prevent risks
Prophylactic anticoagulant therapy
How do you reduce the risk of recurrence?
lower procoagulant factors
e.g.: warfarin, DOACs
increase anticoagulant activity
e.g: heparin
When is therapeutic anticoagulation used?
Venous thrombosis
Initial treatment to minimise clot extension/embolisation (< 3 months)
Long term treatment to reduce risk of recurrence
Atrial fibrillation:
800 per 100 000 population potentially eligible in 1 year
To reduce risk of embolic stroke
Mechanical prosthetic heart valve
When is thromboprophylaxis used?
following surgery, during hospital admission, during pregnancy
What are the main features of heparin?
Naturally occurring glycosaminoglycan
Produced by mast cells of most species
Porcine products used in UK
Varying numbers of saccharides in chains – differing lengths
- Long chains - Unfractionated (UFH) – intravenous administration, short half life
- Low molecular weight (LMWH) – subcutaneous administration
What are the actions of unfractionated heparin?
Enhancement of Antithrombin
Changing the active site of antithrombin
Far greater affinity for target proteases (FXa and thrombin)
Inactivation of thrombin (Hep binds AT + Thrombin)
Inactivation of FXa (Hep binds AT only)
(Inactivation of FIXa, FXIa, FXIIa)
What is the action of low-molecular weight heparin?
Predominantly against FXa
Shorter chains are not long enough to wrap around thrombin and antithrombin
What is the effect of unfractionated heparin on test?
Prolongation of APTT
How does Warfarin work?
Competes with Vitamin K – complicated metabolism
Many dietary, physiological and drug interactions
Narrow therapeutic index and requires monitoring
Reduces production of functional coagulation factors
Induces an anticoagulated state slowly
Reversible
How is the action of Warfarin reversed?
Reversed slowly by Vit K administration – takes several hours to work
Reversed rapidly by infusion of coagulation factors:
PCC (Prothrombin Complex Concentrate- contains Factors II, VII, IX and X)
FFP (Fresh Frozen Plasma)
What are side effects of Warfarin?
Bleeding Minor 5% pa Major 0.9 – 3.0% pa Fatal 0.25% pa Skin Necrosis Purple toe syndrome Embryopathy – Chondrodysplasia punctata
What are the features of skin necrosis?
Skin Necrosis
Severe Protein C deficiency
2-3 days after starting Warfarin
Thrombosis predominantly in adipose tissues
What are the features of purple toe syndrome?
Disrupted atheromatous plaques bleed
Cholesterol emboli lodge in extremities
What is chondrodysplasia punctata?
Early fusion of epiphyses
Warfarin teratogenic in 1st trimester
How do you monitor warfarin?
International Sensitivity Index
Indicates sensitivity of particular thromboplastin for warfarin
Unanticoagulated normal INR = 1.0
Target INR usually 2-3
What can cause resistance to warfarin?
Lack of patient compliance
Measure warfarin levels
Proteins Induced by Vitamin K Absence (PIVKA)
Diet, Increased Vit K intake
Increased metabolism Cyt P450 (CYP2C9)
Reduced binding (VKORC1)
What would you give for initial treatment to minimise clot extension (< 3 months)?
DOAC or LMWH for first few days followed by DOAC or warfarin
What would you give for long term treatment to reduce risk of recurrence?
DOAC or warfarin
What would you give for AF?
DOAC or warfarin
What would you give for mechanical prosthetic heart valve?
Warfarin (DOACs not effective and should be avoided)
What would you give following surgery?
LMWH or DOAC
What would you give during pregnancy?
LMWH (DOACs not safe in pregnancy)
How would you tip the balance towards venous thrombosis?
Decreased fibrinolytic factors
Decreased anticoagulant factors
Increase coagulant factors
Increase platelets
How would you tip the balance towards
Increased fibrinolytic factors
Increased anticoagulant factors
Decrease coagulant factors
Decrease platelets
